Methyl 2-cyano-3,11-dioxo-18b-olean-1,12-dien-30-oate (CDODAMe) is a synthetic derivative of glycyrrhetinic acid, a triterpenoid phytochemical found in licorice extracts. CDODA-Me inhibited growth of RKO and SW480 colon cancer cells and this was accompanied by decreased expression of Sp1, Sp3 and Sp4 protein and mRNA and several Sp-dependent genes including survivin, vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1 or Flt-1). CDODA-Me also induced apoptosis, arrested RKO and SW480 cells at G 2 /M, and inhibited tumor growth in athymic nude mice bearing RKO cells as xenografts. CDODA-Me decreased expression of microRNA-27a (miR-27a), and this was accompanied by increased expression of 2 miR-27a-regulated mRNAs, namely ZBTB10 (an Sp repressor) and Myt-1 which catalyzes phosphorylation of cdc2 to inhibit progression of cells through G 2 /M. Both CDODA-Me and antisense miR-27a induced comparable responses in RKO and SW480 cells, suggesting that the potent anticarcinogenic activity of CDODA-Me is due to repression of oncogenic miR-27a. ' UICCKey words: CDODA-Me; anticarcinogenicity; miR-27a; colon cancer; cell cycle MicroRNAs (miRNAs) are 20-25 bp oligonucleotides that interact with complementary binding sites in 3 0 -untranslated regions of target mRNAs to inhibit their expression by blocking translation or by decreasing mRNA stability.1,2 miRNA interactions with mRNA requires the overlap of 6-8 base pairs and, due to this relatively low stringency, computational studies show that miRNAs can potentially interact with several hundred mRNAs.Despite this lack of specificity, miRNAs have a profound effect on gene expression and cellular homeostasis and, in cancer cells, expression of several critical oncogenes and tumor suppressor genes are regulated by miRNA expression.3-6 miR-221 and miR-222 target the cyclin-dependent kinase inhibitor p27 6 and miR-21 decreases expression of several mRNAs including the tumor suppressor gene tropomyosin 1. 3 Recent studies in this laboratory showed that miR-27a targets ZBTB10 mRNA, a putative zinc finger protein that suppresses specificity protein (Sp) transcription factors and Sp-dependent gene expression. 7 The Sp transcription factors Sp1, Sp3 and Sp4 are highly expressed in cancer cell lines, and results of RNA interference studies show that Sp proteins regulate expression of angiogenic genes such as vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR1, Flt-1), VEGFR2 (KDR) and the antiapoptotic gene survivin. 8-14Betulinic acid and the nonsteroidal anti-inflammatory drug tolfenamic acid inhibit prostate and pancreatic cell and tumor growth through activation of proteasome-dependent degradation of Sp1, Sp3 and Sp4 proteins. 13,14 In our study, we show that methyl 2-cyano-3,11-dioxo-18b-olean-1,12-dien-30-oate (CDODA-Me) is highly cytotoxic to colon cancer cells and also decreases Sp and Sp-dependent genes and proteins. However, these effects are proteasome-independent. We now show for the first time that CDODA-Me acts through downregulation of...

MicroRNAs (miRNAs) are a large family of small, non-coding RNAs that play a pivotal role in tumorigenesis. miR‑34a, which is a member of the miR-34 family, is a downstream target of p53. Increasing evidence shows that miR-34a dysregulation may contribute to tumor development and progression in numerous cancers, including esophageal squamous cell carcinoma (ESCC). However, the mechanism of miR-34a in the regulation of ESCC cells need to be further elucidated because of the complex regulative network of miRNAs. The miR-34a expression in ESCC samples has been confirmed using quantitative reverse transcription polymerase chain reaction. The effects of miR-34a on cell migration and invasion were examined in ESCC cell lines using wound healing and Transwell assays, respectively. The effects of miR-34a on matrix metalloproteinase (MMP)-2 and -9 and fibronectin type III domain containing 3B (FNDC3B) expression levels were detected by luciferase reporter assays and western blot analysis. Quantitative polymerase chain reaction revealed that the miR‑34a expression is significantly downregulated in the ESCC tissues compared to that in the adjacent normal tissues. miR-34a overexpression was significantly suppressed migration and invasion in the ESCC cells and simultaneously inhibited the MMP-2, MMP-9 and FNDC3B expression levels by targeting the coding and 3'-untranslated regions, respectively. The findings indicated that microRNA‑34a suppresses cell migration and invasion by targeting MMP-2, MMP-9, and FNDC3B in ESCC.

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Background: Adults with chronic conditions such as heart disease, diabetes, or lung disease are more likely to develop complications from a number of vaccine-preventable diseases, including influenza and pneumonia. In this study, we use the data from a chronic disease management information system in Shanghai to estimate vaccination coverage and characterize predictors of seasonal influenza and 23-valent pneumococcal polysaccharide vaccine (PPSV23) vaccination among people with chronic disease in Shanghai. Methods: The Shanghai Centers for Disease Control and Prevention have information systems related to chronic disease management, hospital records, and immunizations. Data from individuals with hypertension, diabetes and chronic obstructive pulmonary disease (COPD) were abstracted during July 2017. The main outcome was coverage of pneumococcal and influenza vaccination. Vaccination coverage was calculated across demographic groups. Significance in bivariate associations was assessed through Pearson's chi-square tests, and in multivariable models through logistic regression models with a forward stepwise method to select variables. Results: In the sample of 2,531,227 individuals ≥15 years, 22.8% were vaccinated for pneumonia from

Cerebral ischemia/reperfusion (I/R) injury-induced cellular apoptosis contributes to neuronal death in ischemic stroke, while endoplasmic reticulum stress (ERS) and subsequently triggered unfolded protein response (UPR) are the major mechanisms of cerebral I/R injury-induced apoptosis. A number of studies indicated that apelin-13 protects neurons from I/R injury-induced apoptosis. Apelin-36, the longest isoform of apelin, has stronger affinity to apelin receptor than apelin-13 does. However, the role of apelin-36 in ischemic stroke is less studied. In addition, preventive administration of apelin was applied in most studies, which could not precisely reflect its therapeutic potential in ischemic stroke. Here, we first reported that low dose of apelin-36, other than apelin-13, administrated after ischemic stroke significantly reduced infarct volume in rats. Moreover, apelin-36 attenuated cerebral I/R injury-induced apoptosis and caspase-3 activation. Furthermore, apelin-36 suppressed I/R injury-induced CHOP and GRP78 elevation, indicating that apelin-36 inhibited ERS/UPR activation. Our study first demonstrated that post-stroke administration of low-dose apelin-36 could attenuate cerebral I/R injury-induced infarct and apoptosis, which is associated with the inhibition of cerebral I/R injury-induced ERS/UPR activation. Our data support the therapeutic potential of apelin-36 in ischemic stroke although further investigation is needed.

Deletion analysis of several 17b-estradiol (E 2 )-responsive genes have identified GC-rich sites that are associated with hormone-induced transactivation in MCF-7 breast cancer cells. However, the role of individual specificity proteins (Sps) in mediating hormone-induced gene expression has not been unequivocally determined. In transient transfection studies using E 2 -responsive GC-rich promoters from the E 2 F1, carbamoylphosphate synthetase/aspartate transcarbamylase/dihydroorotase (CAD), and retinoic acid receptor a (RARa) genes, RNA interference using small inhibitory RNAs for Sp1 (iSp1), Sp3 (iSp3), and Sp4 (iSp4) decreased both basal and E 2 -induced transactivation. The contributions of individual Sp proteins to basal and E 2 -induced activity were promoter dependent. iSp1, iSp3, and iSp4 also significantly inhibited hormonal induction of E 2 F1, CAD, and RARa mRNA levels; however, the enhanced inhibitory effects of the latter two small inhibitory RNAs suggest that Sp3 and Sp4 play a major role in estrogen receptor a/Sp-mediated gene expression in MCF-7 cells.